Erythrocyte
glutathione depletion has been linked to
hemolysis and oxidative stress.
Glutamine plays an additional
antioxidant role through preservation of intracellular
nicotinamide adenine dinucleotide phosphate (
NADPH) levels, required for
glutathione recycling. Decreased
nitric oxide (NO) bioavailability, which occurs in the setting of increased
hemolysis and oxidative stress, contributes to the pathogenesis of
pulmonary hypertension (PH) in
sickle cell disease (SCD). We hypothesized that altered
glutathione and
glutamine metabolism play a role in this process. Total
glutathione (and its precursors) and
glutamine were assayed in plasma and erythrocytes of 40 SCD patients and 9 healthy volunteers. Erythrocyte total
glutathione and
glutamine levels were significantly lower in SCD patients than in healthy volunteers.
Glutamine depletion was independently associated with PH, defined as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/s. The ratio of erythrocyte
glutamine:
glutamate correlated inversely to TRV (r = -0.62, P < .001), plasma
arginase concentration (r = -0.45, P = .002), and plasma-free
hemoglobin level (r = -0.41, P = .01), linking erythrocyte
glutamine depletion to dysregulation of the
arginine-NO pathway and increased hemolytic rate. Decreased erythrocyte
glutathione and
glutamine levels contribute to alterations in the erythrocyte redox environment, which may compromise erythrocyte integrity, contribute to
hemolysis, and play a role in the pathogenesis of PH of SCD.